In the repair of a dental bone defect such as periodontal bone loss, a treatment may include application of a composition or formulation to the defect site to enhance repair and bone healing. The composition typically includes: (1) a particulate material to provide structural support and filling of the defect; (2) compounds or medicaments to enhance repair of bone; and (3) a carrier system to facilitate delivery to and retention of the composition at the defect site for the duration of the treatment.
Selection of the particulate material depends upon its intended function in the treatment, its biocompatibility with the human body and its availability. A key limitation is whether the function of the treatment requires that the material be resorbed by natural bodily actions or remain in place as permanent supporting structures. Many formulations such as those described by Hubbard in U.S. Pat. No. 5,922,025 and related patents intend to deliver, by injection, a tissue augmentation material that is non-resorbable, for example comprising a ceramic particulate of 15-150 μm, suspended in a resorbable polysaccharide gel carrier, such as hyaluronic acid. The non-resorbable ceramic particulate is intended to effect a one-time, permanent repair that does not require repetitious treatments. Other such materials include bioactive/biocompatible glass particulates, such as described by Walker et al in WO 91/17777, also comprising an injectable gel formed of a hyaluronic acid, of at least 106 daltons molecular weight. See also Hench et al in U.S. Pat. No. 5,840,290 and related patents, wherein a glass particulate is said to bond to bone at the defect site, enhancing osseous ingrowth or infiltration for repair.
Where it is desired to generate new bone to repair a defect and where immediate and continued structural support is not a limiting factor, regeneration of bone by natural body mechanisms is most desirable. The natural repair and regeneration process has long been thought to be enhanced by filling the defect with various bone derived or bone-related synthetic particulates. Gerber in German Patent Application DE 100 60 036 describes a “remodeling” mechanism wherein bone is resorbed and replaced by osteoclasts by processes termed “osteogenesis”, “osteoconduction” and “osteoinduction”. Gerber describes osteoconduction as bone growth arising from bone tissue that is present along a leading structure thereof; osteoinduction as a stimulation of differentiation of non-bone cells to form osteoblasts; and osteogenesis as a new formation of bone from vital, transplanted bone cells.
Gerber notes that resorbability is an essential requirement for a material that is to participate in remodeling and be replaced by natural bone within a certain time without an inflammation reaction that inhibits formation of tissue.
Of the useful bone particulates, autologous derived material, while effective and safe, is of impractical availability generally. Allogenic material is readily available and, alternatively, xenogeneic bone sources are utilized as well. Synthetic materials, principally hydroxyapatite are also available.
The various particulate bone derived materials may include naturally occurring organic components that function to induce and mediate replacement bone growth. However, there are concerns for biocompatibility and safety in allowing organic components to remain in the bone particulate material. Hence, the bone particulate may be treated by a sintering process to reduce such risks. Alternatively, the bone particulate source material may be replaced by a completely synthetic hydroxyapatite material that includes no organic residue. The difficulty arising for synthetics is that the resulting material may not resorb or otherwise lacks activity in the remodeling process.
Some researchers have focused upon providing bone or substitute particulates that have porous structures that enhance bone growth or integration. Thus, Ewers et al in U.S. Pat. No. 4,770,860 describe a resorbable porous hydroxyapatite material, derived from a lime-containing algae by means of a hydrothermal process in the presence of phosphates. In Ewers et al U.S. Pat. No. 6,428,803, the hydroxyapatite material is provided in the form of a gel obtained by a unique sol-gel process.
In the previously mentioned German Patent Application DE 100 60 036, Gerber describes a resorbable bone replacement material based upon calcium phosphates wherein the material is characterized by a “loose” crystal structure. The structure further includes various sized interconnecting pores that encourage ingrowth of collagen fibers to initiate the remodeling process.
Formulations thought to enhance repair of bone tissue may include bone growth agents. Bhatnagar in U.S. Pat. No. 5,635,482 describes a synthetic collagen-like agent that mimics autogenous cell attachment factors that promote bone growth. Bhatnagar identified and synthesized a fifteen amino acid sequence of Type I collagen that promotes migration of reparative cells from surrounding tissues; directs cell attachment and oriented migration; and facilitates a biomimetic environment for bone generation. These and related polypeptide materials, called P-15, are bound to a particulate hydroxyapatite which may be a natural, microporous xenogeneic bone mineral, such as OsteoGraf® N-300 manufactured by Dentsply Friadent CeraMed of Lakewood, Colo. In order for the P-15 cell binding poly peptide to be active, it must be bound irreversibly to the particulate. Bhatnagar teaches that the resulting dry particulate matrix including P-15, trade marked PEPGEN P-15® Bone Graft and sold by Friadent CeraMed may be combined with a carrier such as PBS or a hydrogel for placement, for example, in an intrabony defect in a tooth supporting structure.
The literature includes a number of formulations including other “growth factors” that function differently from P-15, in that the factors are not bound to the particulate but in solution. Radomsky in U.S. Pat. No. 5,942,499 and related patents claim increasing bone growth rate or magnitude directly, without the presence of active bone particulates or the like, by combining bFGF with hyaluronic acid. Radomsky distinguishes his formulation from the known effectiveness of demineralized bone matrix (DBM) alone or DBM in combination with hyaluronic acid. Radomsky claims enhancing bone repair, depending solely upon the combination of bFGF with hyaluronic acid to promote growth amount. Gertzmann et al in U.S. Pat. No. 6,030,635 utilizes an allogenic bone particulate that is demineralized comprising essentially collagen, further containing active “bone morphogenic proteins” (BMP), wherein the resulting formulation is said to be osteoconductive and osteoinductive, with the DBM particulate being remodeled into natural bone. The formulation includes less than about 50% by weight DBM suspended in hyaluronic acid, having a molecular weight of 7×105-3×106 daltons, to form a hydrogel that is a malleable putty. Higher concentrations of DBM in the Gertzmann formulation result in poor formability, too grainy and too dry for convenient placement.
In general, formulators of bone treatment materials have directed a great deal of effort to improve handling characteristics through selection of an appropriate carrier for delivering the bone repair material to the defect site. It is desirable that the bone repair material be easily placed, but not be allowed to migrate from the defect. In addition, and primarily, bone formation must not be inhibited by the carrier. That is, the carrier materials for the bone repair material must be biocompatible and not interfere with the mediated bone formation, while helping provide adequate spacing between the repair material particulates to allow for cell and vascular infiltration. The carrier material should biodegrade and be resorbed. However, too fast a degradation rate is not preferred since cellular and vascular infiltration cannot develop. Too slow of a resorption rate also interferes with cellular migration, vascular penetration and bone formation.
As described by Bhatnagar, as well as the others cited above, preferred carriers are hydrogels that incorporate the bone particulate and any growth enhancing agent. Preferred hydrogels include polysaccharides, particularly those of high molecular weight, preferably greater than 106 daltons. A most particularly preferred carrier is hyaluronic acid and its derivatives. While much of the prior systems have required injectability as a key handling characteristic, compositions that have a putty consistency are particularly useful in treating periodontal and related bone loss defects.
In a typical periodontal surgical bone repair procedure or method, an incision is made in the gum tissue to expose a bone defect adjacent to a tooth root. Once the defect and root are debrided, a bone repair material, such as the aforementioned PEPGEN P-15 bone graft material, suspended in a suitable carrier is placed. The gum tissue is then closed, maintaining the repair material in place. See Bowen et al in “Comparison of Decalcified Freeze-Dried Bone Allograft and Porous Particulate Hydroxyapatite in Human Periodontal Osseous Defects”, J. Periodontology (May 1989). Optionally, a barrier material may be utilized to retain the repair formulation in contact with the defect.
There remains a need for bone repair treatment formulations that comprise a putty consistency with high concentrations of resorbable bone or bone-like particulate in a high concentration carrier that when applied to the defect site remains adhered thereto without migration or excessive expansion.